The long term objective of this project is to determine the functions of glial cells (Muller cells and astrocytes) in the mammalian retina. Preliminary studies from our laboratory show that light-evoked neuronal activity can induce calcium increases in retinal gila and that activation of glial cells can either facilitate or depress synaptic transmission onto ganglion cells. The specific aims for the project period are: 1) Identify the mechanisms by which light-evoked neuronal activity elicits calcium increases in retinal glial cells. Hypotheses to be tested include: i) neurotransmitters released from synaptic terminals evoke glial calcium increases, ii) transmitters released from extra-synaptic regions of ganglion cells evoke glial calcium increases. 2) Determine the cellular mechanism by which glial cells hyperpolarize retinal ganglion cells. We will test the hypothesis that glial cells inhibit ganglion cells by opening ganglion cell G-protein coupled inwardly rectifying K+ channels (GIRKs). 3) Identify the mechanisms by which glial cells facilitate synaptic transmission. Hypotheses to be tested include: Gila facilitate synaptic transmission i) by releasing ATP and activating presynaptic P2X, P2Y or A2 receptors, ii) by releasing glutamate and activating presynaptic mGluRs, iii) by releasing D-serine and facilitating postsynaptic NMDA receptors. 4) Identify the mechanisms by which glial cells depress synaptic transmission. Hypotheses to be tested include: Gila depress synaptic transmission i) by releasing ATP and activating presynaptic A1 receptors, ii) by releasing glutamate and activating presynaptic mGluRs, iii) by releasing glutamate and desensitizing postsynaptic GluRs. Glial cells have been implicated in many types of retinal pathology, including diabetic retinopathy, glaucoma and macular degeneration. Knowledge of the basic physiological properties of retinal gila and their interactions with neurons will add to our understanding of how these cells contribute to retinal pathology. The research outlined in this proposal will provide significant progress towards this goal.